Benzodiazepines are a class of antidepressants, anti-panic agents, and muscle relaxants used to ameliorate anxiety, treat panic disorders, induce sleep, relax muscles, and relieve seizures and muscle spasms. Benzodiazepine medications produce these effects by depressing the central nervous system. Clonazepam, alprazolam, chlordiazepoxide, diazepam, lorazepam, oxazepam, estazolam, midazolam, and triazolam are examples of benzodiazepine medications.
Clonazepam is marketed by Hoffman-La Roche under the trade names KLONOPIN® (Hoffmann-La Roche Inc., New Jersey) in the United States and RIVOTRIL® (Hoffmann-La Roche Inc., New Jersey) in Canada, South America, and Europe. The pharmacological profile of clonazepam resembles that of other anxiolytic/sedative benzodiazepine medications, and its anticonvulsive characteristics are like those of other diazepines. Clonazepam can suppress the spike-wave discharge accompanying absence seizures (i.e., petit mal seizures) and reduce amplitude, frequency, duration, and discharge spreading in small-scale motor seizures.
Lorazepam was first introduced in the late 1970's by Wyeth Pharmaceuticals under the trade name Ativan®. It is now manufactured by Wyeth Laboratories, Pennsylvania and distributed by Biovail Pharmaceuticals, New Jersey and is indicated for the management of anxiety disorders or for the short term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Injectable lorazepam is useful as an initial anticonvulsant medication for the control of status epilepticus.
Diazepam was first marketed as Valium® by Hoffman-LaRoche in the 1960's. Valium is now distributed by Roche Pharmaceuticals, New Jersey. Valium is indicated for the management of anxiety disorder and relief of symptoms of anxiety, for symptomatic relief of acute alcohol withdrawal, adjunctively for relief of skeletal muscle spasm, and adjunctively in convulsive disorders.
Clonazepam is well absorbed orally; maximum blood concentrations typically occur in one to two hours. It is metabolized by the liver and reduced to inactive metabolites that are excreted primarily in the urine. The amount excreted unchanged in the urine is less than 0.5% of a dose. In addition, 9% to 27% of a dose of clonazepam is excreted in the feces. Clonazepam exhibits a half-life that varies from about 18 hours to 50 hours.
Lorazepam is well absorbed orally; maximum blood concentrations typically occur in one to four hours. It is metabolized by the liver and reduced to inactive metabolites that are excreted primarily in the urine. Lorazepam exhibits a half-life that varies from about 8 hours to 24 hours.
Diazepam is well absorbed orally; maximum blood concentrations typically occur in one to two hours. It is metabolized by the liver and reduced to inactive metabolites that are excreted primarily in the urine. Diazepam exhibits a half-life of about 100 hours.
Clonazepam exhibits strong anxiolytic properties and euphoric side effects; therefore, it is considered a “highly potent” benzodiazepine. Specifically, 0.25 mg of clonazepam is roughly equal to 1.0 mg of lorazepam and 5.0 mg of diazepam. Clonazepam's sedative effects are relatively weak in comparison with its strong anticonvulsant and anxiolytic effects. The sedative effects of clonazepam are also weaker than that of other benzodiazepines. Clonazepam appears, to act by simulating the central nervous system actions of GABA, like other benzodiazepines.
Clonazepam is commonly prescribed to treat epilepsy, anxiety disorders, panic attacks, Restless Legs Syndrome (RLS), chronic fatigue syndrome, REM behavior disorder, night terrors, and Tourette's Syndrome. In the treatment of anxiety disorders, low-dose, long-term treatment with clonazepam may be required because of the chronic nature of anxiety. Although benzodiazepines have some potential for abuse, the use of clonazepam in long-term treatment of anxiety disorders is therapeutic and should not be confused with dependence or addiction. Clonazepam also is used for the initial treatment of mania in combination with medications such as lithium, risperidone, or haloperidol. In addition, clonazepam is prescribed to treat the symptoms of Parkinson's disease and schizophrenia and for twitching and pain management. Clonazepam has also been used to reduce and manage Tourette's Syndrome motor tics. In another application, clonazepam has been used to treat Hallucinogen Persisting Perception Disorder (HPPD). Clonazepam is not typically used to treat insomnia because of its relatively weak sedative effects.
For epilepsy patients, clonazepam is indicated for use alone or as an adjunct therapy, and as primary therapy and for refractory patients. Epilepsy is a disorder characterized by transient but recurrent disturbances of brain function that may or may not be associated with impairment or loss of consciousness and abnormal movements or behavior. The primary objective of caring for patients with epilepsy is to restore their functional capacity to its maximal potential. To do this, physicians use a stable regimen of anti-epileptic drugs (AED). Approximately 30% of patients continue to be refractory to AED treatment and often have recurrent seizures that may occur in clusters. Some of these patients may also experience continued seizure activity without regaining consciousness for a prolonged period of time, a condition called status epilepticus. In addition to being life threatening, recurrent seizures and status epilepticus can impact cognition and permanently damage other brain function.
Patients with refractory epilepsy including episodes of seizure clusters and status epilepticus often present at the emergency room where they are treated with IV benzodiazepines, phenyloin and barbiturates. The goal of treatment in the ER is the prompt cessation of seizure activity. Prior to the ER, there are limited treatment options available to these patients and caregivers.
Epileptic seizures are often classified in two types: primary generalized seizures, (seizures that begin with a widespread electrical discharge involving both sides of the brain) and partial seizures (seizures involving one area of the brain). Included among primary generalized seizures are: absence (also known as petit-mal) seizures, myoclonic seizures, atonic and tonic seizures, clonic and clonic-tonic (also known as grand-mal) seizures. Included among partial seizures are simple and complex seizures and secondary generalized seizures.
Clonazepam has been used in the treatment many different epilepsy syndromes and for different types of seizures including Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. Clonazepam is also useful in patients with absence seizures. In Europe, clonazepam, available in IV formulation, is also used in the acute treatment of seizures in the emergency setting. Often patients with history of cluster seizures and status epilepticus will present to the emergency room.
A rectal gel formulation of diazepam is commercially available (Diastat®) for outpatient treatment of increased seizure activity in patients on stable anti-epileptic drug regimen. Diastat® is administered to patients by caregivers and has been effective in aborting seizure activity and thereby reducing ER visits. However, due to the mode of administration, Diastat® has primarily been used in the pediatric population where a parent can rectally administer to their child. Ideally, an outpatient rescue treatment for these epileptic patients would have a quick onset of action terminating the ongoing seizure and prevent recurrence of seizure activity through a long enough duration of effect. The treatment should also be easily administered by caregivers in a culturally acceptable mode of administration that is easily accessible.
The nasal mucosa offers an alternative to oral and parenteral administration; intranasal administration is a practical way to achieve the therapeutic effect of many medications. Advantages of this method are that drugs can be administered readily and simply, and either a localized or a systemic effect can be achieved. Intranasal administration suffers from a significant problem, however: Most drug molecules diffuse slowly and poorly through the nasal mucosa. Therefore, therapeutic levels of the medication cannot be achieved or may not be achieved in time with the progression of the incidence. A further constraint is that the administration volume must be small; usually it is maximally about 150 μL per nostril. If a greater volume of medication is administered, it may drain into the pharynx and be swallowed.
Various intranasal benzodiazepine compositions have been developed. However, some of these compositions exhibit a delayed time to peak plasma concentration, poor absorption, or poor bioavailability. This is unacceptable for treatment or prevention of some disorders, illnesses and symptoms. Some intranasal midazolam formulations, for example, are produced at a pH that causes nasal irritation and burning in many patients.
Accordingly, there is a need for intranasal benzodiazepine compositions with improved properties such as, for example, rapid absorption, time to peak concentration, and bioavailability. Further, a need exists for vehicles in which the solubility of the drug is high but which are non-damaging to the nasal mucosa. There also is a need for intranasal compositions that improve patient compliance.